ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.1178A>C (p.His393Pro)

gnomAD frequency: 0.00003  dbSNP: rs118203944
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000424623 SCV000517248 pathogenic not provided 2015-05-27 criteria provided, single submitter clinical testing The H393P variant in the ARSB gene is a common MPS VI variant that has been reported in thehomozygous and the compound heterozygous state in multiple unrelated individuals withmucopolysaccharidosis type VI (MPS VI). Patients with the H393P variant who were compoundheterozygous for different missense variants were reported with variable disease severity (Litjens et al.,1996; Karageorgos et al., 2007). Functional studies of the H393P substitution indicate that it is a severe nullallele resulting in an undetectable enzyme level (Litjens et al., 1996). The H393P variant was notobserved with any significant frequency in approximately 6500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variantin these populations. The H393P variant is a non-conservative amino acid substitution, which occurs at aposition that is conserved across species. Missense variants in nearby residues (E390K and F399L) havebeen reported in the Human Gene Mutation Database in association with MPS VI (Stenson et al., 2014),supporting the functional importance of this region of the protein. We interpret H393P as a pathogenic variant.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000000934 SCV000802966 uncertain significance Mucopolysaccharidosis type 6 2018-01-01 criteria provided, single submitter curation Very low frequency in ExAC (PM2); Reputable source identifies as pathogenic (PP5)
Invitae RCV000000934 SCV001234817 pathogenic Mucopolysaccharidosis type 6 2021-10-27 criteria provided, single submitter clinical testing This sequence change replaces histidine, a(n) basic and polar amino acid, with proline, a(n) neutral and non-polar amino acid, at codon 393 of the ARSB protein (p.His393Pro). This variant is present in population databases (rs118203944, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 11939792, 17458871). ClinVar contains an entry for this variant (Variation ID: 886). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSB protein function. Experimental studies have shown that this missense change affects ARSB function (PMID: 8651289). This variant disrupts the p.His393 amino acid residue in ARSB. Other variant(s) that disrupt this residue have been observed in individuals with ARSB-related conditions (PMID: 26609033, 27826022), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000934 SCV000021084 pathogenic Mucopolysaccharidosis type 6 1996-06-01 no assertion criteria provided literature only
Natera, Inc. RCV000000934 SCV001457624 pathogenic Mucopolysaccharidosis type 6 2020-09-16 no assertion criteria provided clinical testing

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